ClinVar Miner

Submissions for variant NM_013382.7(POMT2):c.1238G>C (p.Arg413Pro)

gnomAD frequency: 0.00001  dbSNP: rs190285831
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000081563 SCV000113494 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing
Invitae RCV001240349 SCV001413284 likely pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2; Autosomal recessive limb-girdle muscular dystrophy type 2N 2023-11-10 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 413 of the POMT2 protein (p.Arg413Pro). This variant is present in population databases (rs190285831, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 17878207, 26013959, 26886200, 28973083, 29175898, 36048137). ClinVar contains an entry for this variant (Variation ID: 3225). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMT2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity RCV000081563 SCV003809750 uncertain significance not provided 2023-03-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000003381 SCV004204100 likely pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 2023-09-06 criteria provided, single submitter clinical testing
New York Genome Center RCV001240349 SCV005044153 likely pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2; Autosomal recessive limb-girdle muscular dystrophy type 2N 2022-10-21 criteria provided, single submitter clinical testing The c.1238G>C variant in POMT2 has previously been reported in compound heterozygous state in individuals with Walker-Warburg syndrome (WWS), muscle-eye-brain disease (MEB) and limb-girdle muscular dystrophy (LGMD) patients [PMID: 17878207, 36048137, 28973083, 31980526, 29175898, 30060766, 32528171] and it has been deposited in ClinVar [ClinVar ID: 3225] as Variant of Uncertain Significance. The c.1238G>C variant is observed in 16 alleles (~0.0020% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.1238G>C variant in POMT2 is located in exon 11 of this 21-exon gene and predicted to replace an evolutionarily conserved arginine amino acid with proline at position 413 in the MIR domain [PMID: 34413876] of the encoded protein. In silico predictions are in favor of damaging effect for p.(Arg413Pro) [(CADD v1.6 = 31, REVEL = 0.981)]; however, there are no functional studies to support or refute these predictions. Variants nearby p.(Arg421Trp) within the kinase domain have been reported in the literature [PMID: 34413876] and ClinVar [ClinVar ID: 162597] in individuals with POMT2-related a-dystroglycanopathy. Based on available evidence this inherited c.1238G>C p.(Arg413Pro) variant identified in POMT2 is classified here as Likely Pathogenic.
OMIM RCV000003381 SCV000023539 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 2007-10-01 no assertion criteria provided literature only

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